Activity of the polyamine-vectorized anti-cancer drug F14512 against pediatric glioma and neuroblastoma cell lines
| Autor: | Nicolas Guilbaud, Thierry Sarrazin, Eric Lartigau, Anna Kruczynski, Pierre Leblond, Elodie Boulet, Christine Bal-Mahieu, Samuel Meignan, Amélie Lansiaux, Christian Bailly, Arnaud Pillon |
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| Rok vydání: | 2014 |
| Předmět: |
Cell Survival
Cell Antineoplastic Agents Pharmacology Biology Carboplatin chemistry.chemical_compound Neuroblastoma Glioma Cell Line Tumor Radiation Ionizing medicine Animals Humans Pharmacology (medical) Cytotoxicity Melphalan Etoposide Podophyllotoxin Cisplatin Mice Inbred BALB C Polyamine transport Liver Neoplasms medicine.disease medicine.anatomical_structure Oncology chemistry Female Spermine medicine.drug |
| Zdroj: | Investigational new drugs. 32(5) |
| ISSN: | 1573-0646 |
| Popis: | The poor prognosis of children with high-grade glioma (HGG) and high-risk neuroblastoma, despite multidisciplinary therapeutic approaches, demands new treatments for these indications. F14512 is a topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells via the Polyamine Transport System (PTS) and increases topoisomerase II poisoning. Here, F14512 was evaluated in pediatric HGG and neuroblastoma cell lines. PTS activity and specificity were evaluated using a fluorescent spermine-coupled probe. The cytotoxicity of F14512, alone or in combination with ionizing radiation and chemotherapeutic agents, was investigated in vitro. The antitumor activity of F14512 was assessed in vivo using a liver-metastatic model of neuroblastoma. An active PTS was evidenced in all tested cell lines, providing a specific and rapid transfer of spermine-coupled compounds into cell nuclei. Competition experiments confirmed the essential role of PTS in the cell uptake and cytotoxicity of F14512. This cytotoxicity appeared greater in neuroblastoma cells compared with HGG cells but appeared independent of PTS activity levels. In vivo evaluation confirmed a marked and prolonged antitumoral effect in neuroblastoma cells. The combinations of F14512 with cisplatin and carboplatin were often found to be synergistic, and we demonstrated the significant radiosensitizing potential of F14512 in the MYCN-amplified Kelly cell line. Thus, F14512 appears more effective than etoposide in pediatric tumor cell lines, with greater efficacy in neuroblastoma cells compared with HGG cells. The synergistic effects observed with platinum compounds and the radiosensitizing effect could lead to a clinical development of the drug in pediatric oncology. |
| Databáze: | OpenAIRE |
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